The S100 proteins comprise a large family of calcium-binding proteins, some of which are expressed at high levels in the nervous system. The S100 proteins have been implicated in a wide variety of functions, such as modulation of enzyme function, alteration of cytoskeletal dynamics, cell adhesion and control of cell cycle progression (Schafer et al., Trends Biochem Sci 21: 134-140, 1996). Expression of S100 protein has been shown to be associated with invasive potential and metastatic spread of tumor cells (Inoue et al., Virchows Arch A422: 351-355, 1993).
The primary structure of S100 proteins is highly conserved (Kligman et al., TIBS 13: 437-443, 1988; and Schaefer et al., TIBS 21: 134-140, 1996). In solutions S100 proteins easily form dimers and cystein residues are not necessary for the noncovalent dimerization of S100 (Mely et al., J. Neurochemistry 55: 1100-1106, 1990; Landar et al., Biochim. Biophys. Acta 1343: 117-129, 1997; and Raftery et al., J Am. Soc. Mass Spectrom. 9: 533-539, 1988). The tertiary structure of S100 proteins has been characterized (Kilby et al., Structure 4: 1041-1052, 1996; Smith et al., Structure 6: 211-222, 1998; Sastry et al., Structure 15: 223-231, 1998; and Matsumura et al, Structure 6: 233-241, 1998). Each S100 monomer contains two EF-hand calcium binding domains (Schafer et al., TIBS 21: 134-140, 1996). Calcium binding results in a conformational alteration and exposure of a hydrophobic patch via which S100 proteins interact with their targets (Smith et al, Structure 6: 211-222, 1998; Sastry et al, Structure 15: 223-231, 1998; Matsumura et al, Structure 6: 233-241, 1998; and Kilby et al., Protein Sci. 6: 2494-2503, 1997).
Intracellular and extracellular activities of S100 proteins have also been described (McNutt, J Cutan. Pathol. 25: 521-529, 1988). Intracellular S100 proteins interact with numerous target proteins and modulate multiple cellular processes regulating cell growth, differentiation, metabolism and cytoskeletal structure (Zimmer et al., Brain Res. Bulletin 37: 417-429, 1995; Schafer et al., TIBS 21: 134-140, 1996; Donato, Cell Calcium 12: 713-726, 1991; and Lukanidin et al., In: Gunter U, Birchmeier W, eds. Current Topics in Microbiology and Immunology: Attempts to Understand Metastasis Formation II. Berlin, Heidelberg: Springer-Verlag 213/II, 171-195, 1996). Extracellular disulfide-linked dimers of S100B protein have been reported to stimulate neurite outgrowth in primary cultures of cerebral cortex neurons (Kligman et al., TIBS 13: 437-443, 1988). Such activity has also been reported for oxidized form of the recombinant S100B protein (Winningham-Major et al., J. Cell Biol. 109: 3063-3071, 1989).
The mts1/S100A4 gene, a member of the S100 gene family, was isolated as a gene specifically expressed in metastatic murine tumor cell lines (Ebralidze et al., Genes Dev. 3: 1086-1092, 1989). Studies of Mts1-transfected non-metastatic murine cell lines and Mts1 transgenic mice both indicate that Mts1 plays an important role in tumor progression (Grigorian et al., Gene 135: 229-238, 1993; Takenaga et al., Oncogene 14: 331-337, 1997; Ambartsumian et al., Oncogene 13: 1621-1630, 1996; and Davies et al., Oncogene 13: 1631-1637, 1996). Mts1 has also been shown to affect the cytoskelton and cell motility (Takenaga et al., Jpn. J Cancer Res. 85: 831-839, 1994) via association with stress fibers (Gibbs et al., J. Biol. Chem. 269: 18992-18999, 1994). The heavy chain of non-muscle myosin (MHC) has been identified as a target for the Mts1 protein (Kriajevska et al., J. Biol. Chem. 239: 19679-19682, 1994).
The present invention identifies, for the first time, the neurogenic function of the Mts1 protein. Accordingly, the present invention provides novel compositions and methods useful for stimulating neurite growth in the treatment of neural damage caused by disease or physical trauma.